Farming and Movement Evaluation Study (FAME) FAME is a case-control study of PD nested in the Agricultural Health Study (AHS), including 115 PD cases and 384 controls. PD diagnosis was verified by movement disorder specialists. Controls were a random sample from the remaining cohort, matched to cases by age, sex, and state. Exposure was evaluated using data from the AHS and from additional telephone interviews. Our initial studies focused on pathophysiologic mechanisms implicated in PD by experimental models and genetic studies, including oxidative stress and mitochondrial dysfunction. PD risk was increased by 2-fold by exposure to pesticides that affect these mechanisms, including the herbicide paraquat and the insecticide rotenone, now used primarily to kill fish. Our results support previous work implicating these mechanisms in PD and provide evidence that certain specific pesticides are associated with PD risk. Personal protective equipment: Protective gloves and workplace hygiene can reduce pesticide exposure. We evaluated whether gloves and hygiene modified the association of PD with ever-use of the pesticides paraquat, permethrin, rotenone, and trifluralin. 61% of respondents consistently used protective gloves and 87% consistently used at least 2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among protective glove users, while both pesticides were associated with 4-fold increase in PD risk among non-users. Rotenone was associated with PD regardless of glove use. Trifluralin increased PD risk among people who used fewer than 2 hygiene practices but not among those using 2 or more practices (interaction p=0.02). Thus protective glove use and hygiene practices may reduce risk of PD associated with certain pesticides. Peptidoglycan recognition proteins (PGRPs) and PD: Increased gut permeability, inflammation, and colonic alpha-synuclein pathology are present in early PD and may contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. PGRPs maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that PGRP genetic variants are associated with PD risk. We genotyped 30 SNPs in the four PGLYRP genes. Three of seven PGLYRP2 SNPs, one of five PGLYRP3 SNPs, and six of nine PGLYRP4 SNPs were significantly associated with PD risk. Association was strongest for PGLYRP4 5-prime untranslated region SNP rs10888557 (GG reference, CG OR 0.6 95%CI 0.4-0.9, CC OR 0.15 95%CI 0.04-0.6; log-additive P-trend, 0.0004). These results are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD. Studies in other populations Agricultural Health Study Air pollutants and PD: We evaluated the associations of ozone and fine particulate matter with PD in AHS cohort members. Daily predicted pollutant concentrations were used to derive surrogates of long-term exposure and link them to study participants geocoded addresses. Both pollutants increased PD risk by 30% in North Carolina but not in Iowa. The plausibility of an effect of ambient concentrations of these pollutants on PD risk is supported by experimental data demonstrating damage to dopaminergic neurons at relevant concentrations. NIH-AARP Diet and Health Study Dietary fat and PD: We evaluated the association of dietary fat intake with PD risk. A 124-item food frequency questionnaire was administered at baseline in1995 to 1996, and PD diagnosis was self-reported at the follow-up survey in 2004 to 2006. A total of 1,087 cases with a PD diagnosis between 2000 and 2006 and 299,617 controls were included in the analyses. Overall, intakes of fats and other macronutrients were not associated with PD risk. However, we found a weak positive association between n-6 polyunsaturated adjusting for potential confounders, the odds ratio (OR) and 95% confidence interval (CI) between extreme quintiles of n-6 PUFA intake was 1.23 (95% CI 1.02-1.49, P for trend 0.02). A similar association was observed for the intake of linoleic acid. Results were similar among men and among women. Our study suggests that fat intake in general is not related to the risk for PD. The weak positive association between intake of n-6 PUFA and PD risk needs further investigation. Swedish National Registers PD and cancer: In order to compare cancer occurrence in individuals with and without PD, and between siblings of these individuals, we conducted a family-based matched cohort. We assessed risk of incident cancer in PD patients (N=11,786) versus a matched cohort of PD free individuals (N=58,930) and in siblings of PD patients (N=16,841) versus siblings of PD free individuals (N=84,205). Overall cancer occurrence was 5% higher in PD patients than in PD free individuals, largely due to cancers within 1 year before and after index date for PD, but risk for smoking-related cancers was 13% lower. PD patients had 50% higher risk of melanoma excluding the years immediately before and after the index date. In the sibling comparison, cancer occurrence was largely similar. These results indicate that occurrence of melanoma is higher among PD patients and that mechanisms other than family history explain the association.